Abstract Body: Introduction: Doxorubicin (DOX) is an efficacious antineoplastic agent. However, its clinical application is often limited by its cardiotoxic effects. The immune system, particularly the spleen, plays a critical role in cardiac remodeling. However, the impact of the spleen on the cardiotoxic effects of DOX remains unexplored.
Methods: Six-week-old C57BL/6N male mice were randomly assigned to either control or DOX group. Mice received intraperitoneal injections of either saline or DOX (4 mg/kg/day) for 6 days. To investigate the role of the spleen, a separate experiment was conducted using splenectomized and sham-operated mice, which were similarly treated with saline or DOX. In all experiments, cardiac function was assessed on the 7th day, followed by necropsy on the 8th day. Gene expression analysis of cardiotoxicity and inflammatory markers in the heart was performed using real-time PCR.
Results: DOX significantly reduced cardiac output and ejection fraction, which was accompanied by significant splenic contraction. A strong positive correlation was observed between cardiac output and spleen weight. DOX also caused significant upregulation of cardiotoxicity (atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain 7) and inflammatory (tumor necrosis factor-alpha, calgranulin A (S100A8), calgranulin B (S100A9), interleukin-1beta, and interlukein-1alpha) markers in the heart. In the splenectomy experiment, our results showed that splenectomy modestly reduced cardiac output in DOX-treated mice but also abrogated DOX-induced cardiotoxicity and inflammatory markers in the heart.
Conclusion: The spleen plays a critical role in modulating the cardiotoxic effects of DOX. While splenectomy exacerbates the reduction of cardiac output, it ameliorates DOX-induced markers of cardiotoxicity and inflammation.